DK154763B - PROCEDURE FOR THE PREPARATION OF NORFLOXACIN - Google Patents
PROCEDURE FOR THE PREPARATION OF NORFLOXACIN Download PDFInfo
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- DK154763B DK154763B DK380681A DK380681A DK154763B DK 154763 B DK154763 B DK 154763B DK 380681 A DK380681 A DK 380681A DK 380681 A DK380681 A DK 380681A DK 154763 B DK154763 B DK 154763B
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- carboxylic acid
- fluoro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Description
DK 154763 BDK 154763 B
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af den kendte antimikrobielle forbindelse norfloxacin, der er 1-ætyl-6-fluor-7-( 1-piperazinyl)-4-oxo- 1,4-dihydrokinolin-3-karboxylsyre med formlen 5 0The present invention relates to a particular process for the preparation of the known antimicrobial compound norfloxacin which is 1-ethyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid of formula 5 0
F C00HF C00H
/-\XI jf iv/ - \ XI cf iv
HNHN
ch2ch3 10 i industriel målestok i høj renhed.ch2ch3 10 industrial scale in high purity.
Fremgangsmåde ifølge opfindelsen er ejendommelig ved at man omsætter en 1-ætyl-6-fluor-7-klor-4-oxo-1,4-The process according to the invention is characterized by reacting a 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-carboxylic acid.
dihydrokinolin-3-karboxylsyre med den almene formel Idihydroquinoline-3-carboxylic acid of general formula I
? 1? 1
F COORF COOR
15 jT u T i15 jT u T i
Cl ICl I
ch2ch3CH2CH3
hvor er en lavere alkylgruppe, med piperazin, hvorpå man hydrolyserer den derved vundne forbindelse med den 20 almene formel IIIwhere is a lower alkyl group, with piperazine, upon which the resulting compound of the general formula III is hydrolyzed
? 1 F /V COOR? 1 F / V COOR
nr/ in v_7 ! CH2CH3 25 hvor R har den ovenfor angivne betydning.nr / in v_7! CH 2 CH 3 where R has the meaning given above.
Fra GB patentskrift nr. 2.034.698 er det kendt at fremstille norfloxacin med formel IV ved omsætning af en tilsvarende karboxylsyre med formlen 30 oFrom GB patent specification 2,034,698 it is known to prepare norfloxacin of formula IV by reacting a corresponding carboxylic acid of formula 30
F COOHF COOH
T if T vT if T v
xV/\H S Cl IxV / \ H S Cl I
ch2ch3 i 35 hvor R har den ovenfor angivne betydning, med piperazin. Ved denne betinger dels renheden af udgangsforbindelsen med formel V og dels reaktionsbetingelserne en u- 2ch2ch3 in 35 where R has the meaning given above, with piperazine. In this, on the one hand, the purity of the starting compound of formula V
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behagelig indflydelse på udbyttet af rent norfloxaxin. Rensning af forbindelsen med formel V er nemlig vanskelig på grund af dens ringe opløselighed i forskellige typer opløsningsmidler, således at det er vanskeligt at 5 opnå den rene forbindelse med formel V i industriel målestok.pleasant influence on the yield of pure norfloxaxine. Namely, purification of the compound of formula V is difficult because of its poor solubility in various types of solvents, so that it is difficult to obtain the pure compound of formula V on an industrial scale.
Selv hvis der anvendes renset forbindelse med formel V til fremstilling af norfloxacin, fremkommer der et biprodukt uden nogen antibakteriel virkning, som 10 er vanskelig at fraskille. Det er 1-ætyl-6-(1-piperazi-nyl ).-7-klor-4-oxo-1,4-dihydrokinolin-3-karboxylsyre og har formlenEven if purified compound of formula V is used to prepare norfloxacin, a by-product appears without any antibacterial effect which is difficult to separate. It is 1-ethyl-6- (1-piperazinyl) -7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and has the formula
Nw C00H VI 15 <!:h2ch3 og indebærer i industriel praksis at udbyttet af norfloxacin kun bliver 50-60%.Nw C00H VI 15 <!: h2ch3 and in industrial practice the yield of norfloxacin is only 50-60%.
20 Det har nu overraskende vist sig, at man ved in dustriel fremstilling af norfloxacin i stedet for syren med formel V som udgangsmateriale bruger en 6-fluor-7-klor-4-oxo-1,4-dihydrokinolin-3-karboxylsyreester med formel I, undgår dannelse af biproduktet med formel VI 25 og i det hele opnår den ønskede forbindelse i højt udbytte og i høj renhed, som det er fastslået ved højhastighedsvæskekromatografi (HPLC). Derfor vindes norfloxacin i højt udbytte og kan let renses. Mellemproduktet med formel III er opløseligt i mange opløsningsmidler og 30 kan let renses. Fordelen ved fremgangsmåden ifølge opfindelsen fremgår tydeligt af omstående sammenlignings-eksempel.It has now surprisingly been found that in the industrial preparation of norfloxacin instead of the acid of formula V, a 6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester of formula is used I, avoids formation of the by-product of Formula VI 25 and, on the whole, achieves the desired compound in high yield and in high purity, as determined by high-speed liquid chromatography (HPLC). Therefore, norfloxacin is obtained in high yield and can be easily purified. The intermediate of formula III is soluble in many solvents and can be readily purified. The advantage of the method according to the invention is evident from the above comparative example.
Ved anvendelse af den foreliggende fremgangsmåde opvarmer man i praksis en blanding af udgangsmaterialet 35 med formel I (1 mol), en organisk base og 2-4 mol pipe-razin til en temperatur i området 90-150°C, fortrinsvis 110-120°C i nærværelse eller uden nærværelse af et ikke- 3In practice, using the present process, a mixture of the starting material 35 of formula I (1 mol), an organic base and 2-4 mol of piperazine is heated to a temperature in the range 90-150 ° C, preferably 110-120 ° C. C in the presence or absence of a non-3
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polært opløsningsmiddel. Opvarmningstiden varieres i afhængighed af reaktionstemperaturen; fx kan reaktionen gennemføres på 5 timer ved 110°C. Organiske baser som fx pyridin, pikolin eller triætylamin kan anvendes i reak-5 tionen. Disse organiske baser kan tjene som reaktionsopløsningsmiddel, og mængden af basen kan sænkes når der anvendes et ikke-polært opløsningsmiddel som fx benzen eller toluen.polar solvent. The heating time is varied depending on the reaction temperature; for example, the reaction can be carried out in 5 hours at 110 ° C. Organic bases such as pyridine, picoline or triethylamine can be used in the reaction. These organic bases can serve as the reaction solvent, and the amount of the base can be lowered when a non-polar solvent such as benzene or toluene is used.
Under hydrolysereaktionen kan man anvende en syre, 10 og så er det hensigtsmæssigt at koge mellemproduktet med formel III under tilbagesvaling i en blanding af en mineralsyre såsom saltsyre og en organisk syre såsom eddikesyre. Hvis man i hydrolysereaktionen anvender et alkali, opvarmes mellemproduktet med formel III i en tynd 15 natriumhydroxydopløsning til en temperatur på mellem 50 og 100°C, fortrinsvis til 90-95°C. Hydrolysereaktionen med syre kræver flere timer, men reaktionen under anvendelse af alkali gennemføres på få minutter.During the hydrolysis reaction, an acid may be used, and then it is convenient to boil the intermediate of formula III under reflux in a mixture of a mineral acid such as hydrochloric acid and an organic acid such as acetic acid. If an alkali is used in the hydrolysis reaction, the intermediate of formula III is heated in a thin sodium hydroxide solution to a temperature of between 50 and 100 ° C, preferably 90-95 ° C. The acid hydrolysis reaction requires several hours, but the reaction using alkali is completed in a few minutes.
Fremgangsmåden ifølge opfindelsen belyses først 20 ved nedennævnte sammenligningseksempel og derpå ved nogle udførelseseksempler.The process according to the invention is first illustrated by the comparative examples below and then by some exemplary embodiments.
Sammenligningseksempel 2!- l-Ætyl-6-fluor-7-( 1-piperazinyl)-1,4-dihydro-4- oxokinolin-3-karboxylsyre (Norfloxacin; NFLX', r-INN) blev fremstillet dels ved den kendte teknik ud fra syren med formel V og dels ved fremgangsmåden ifølge opfindelsen ud fra en karboxylsyreester med formel I; 2Q fremstillingen skete i begge tilfælde i teknisk målestok.Comparative Example 2 - 1-Ethyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Norfloxacin; NFLX ', r-INN) was prepared partly by the prior art from the acid of formula V and partly by the process of the invention from a carboxylic acid ester of formula I; In both cases, the production of 2Q was done on a technical scale.
A)_Fremstilling på kendt måde a) 1-Ætyl-6-fluor-7-klor-1,4-dihydro-4-oxokinolin-3-35 ________________________________________ 160,4 kg natriumhydroxyd opløstes i 2600 1 vand og opløsningen opvarmedes til 90°C. Der sattes 330 kg 4A) Preparation in known manner a) 1-Ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-35 160.4 kg of sodium hydroxide was dissolved in 2600 liters of water and the solution heated to 90 ° C. 330 kg of 4 were added
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ætyl-1-ætyl-6-fluor-7-klor-1,4-dihydro-4-oxokinolin-3-karboxylsyre til denne opløsning og der omrørtes i 10 minutter ved 90°C. Efter afkøling neutraliseredes reaktionsblandingen med koncentreret saltsyre. De resulte-5 rende krystaller opsamledes ved filtrering ved hjælp af en centrifuge. Denne filtrering tog 12 timer. Krystallerne dehydratiseredes azeotropt med 200 1 toluen og krystallerne tørredes ved hjælp af en vifte i 8 timer ved 80°C til frembringelse af 267,5 kg (89,5%) 1-ætyl-6-fluor-10 7-klor-1,4-dihydro-4-oxokinolin-3-karboxylsyre.ethyl-1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid to this solution and stirred for 10 minutes at 90 ° C. After cooling, the reaction mixture was neutralized with concentrated hydrochloric acid. The resulting crystals were collected by filtration using a centrifuge. This filtration took 12 hours. The crystals were azeotropically dehydrated with 200 L of toluene and the crystals dried by a fan for 8 hours at 80 ° C to give 267.5 kg (89.5%) of 1-ethyl-6-fluoro-10-7-chloro-1. 4-dihydro-4-oxokinolin-3-carboxylic acid.
!?1_Μ2ϊ£ΐ2?£§2Ϊ2!? 1_Μ2ϊ £ ΐ2? £ §2Ϊ2
En blanding af 260,4 kg 1-ætyl-6-fluor-7-klor- 1,4-dihydro-4-oxokinolin-3-karboxylsyre og 420 kg pipe-15 razm i 587 1 3-metoxy-1-butanol opvarmedes under omrøring og ved hjælp af en elektrisk opvarmer i en time til 140°C. Efter afkøling opsamledes de dannede krystaller ved filtrering under anvendelse af en centrifuge.A mixture of 260.4 kg of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 420 kg of piperazin in 587 l of 3-methoxy-1-butanol was heated. with stirring and with the aid of an electric heater for one hour to 140 ° C. After cooling, the crystals formed were collected by filtration using a centrifuge.
Denne centrifugale filtrering tog 5 timer. De rå kry- 20 staller opløstes i en blanding af 112 1 iseddikesyre og 980 1 vand, og efter behandling med 4 kg aktiveret kul filtreredes opløsningen ved hjælp af et "Spakler" filter af type UR-17-12 (fremstillet af Nippon Dyeing Machine 2This centrifugal filtration took 5 hours. The crude crystals were dissolved in a mixture of 112 l glacial acetic acid and 980 l water, and after treatment with 4 kg of activated charcoal the solution was filtered using a "Spackler" filter of type UR-17-12 (manufactured by Nippon Dyeing Machine 2
Manufacturing Co., Ltd.; filterdimensioner 3m). Denne 25 filtrering tog 11 timer.Manufacturing Co., Ltd.; filter dimensions 3m). This filtration took 11 hours.
Filtratet reguleredes til pH 7,5 med 10%s vandig natriumhydroxydopløsning. De resulterende krystaller opsamledes ved filtrering ved hjælp af en centrifuge, vaskedes med vand og dehydratiseredes azeotropt med 1300 30 1 toluen. Krystallerne tørredes ved hjælp af en vifte i 5 timer ved 80°C. Det tørrede krystrallinske produkt opløstes i 1200 1 dimetylsulfoxid (DMSO) under opvarmning, og efter afkøling opsamledes de afsatte krystaller ved filtrering ved hjælp af en centrifuge. Krystal-35 lerne suspenderedes i 100 1 metanol, omrørtes i 1 time og opsamledes ved filtrering ved hjælp af en centrifuge.The filtrate was adjusted to pH 7.5 with 10% aqueous sodium hydroxide solution. The resulting crystals were collected by filtration using a centrifuge, washed with water and dehydrated azeotropically with 1300 l of toluene. The crystals were dried by a fan for 5 hours at 80 ° C. The dried crystalline product was dissolved in 1200 L of dimethyl sulfoxide (DMSO) under heating and after cooling, the deposited crystals were collected by filtration by centrifuge. The crystals were suspended in 100 L of methanol, stirred for 1 hour, and collected by filtration by centrifuge.
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Krystallerne omkrystalliseredes fra en blanding af di-klormetan/actanol 5:3 og omkrystalliseredes på ny fra ovennævnte blanding og tørredes ved hjælp af en vifte i 8 timer ved 80°C; der vandtes 212,5 kg (67,9%) norfloxa-5 xin.The crystals were recrystallized from a dichloromethane / actanol 5: 3 mixture and recrystallized from the above mixture and dried by a fan for 8 hours at 80 ° C; 212.5 kg (67.9%) of norfloxa-5 xine were obtained.
Bj_Fremgangsmåden" ifølge opfindelsenThe method of the invention
En blanding af 241,5 kg ætyl-1-ætyl-6-fluor-7-klor-1,4-dihydro-4-oxokinolin-3-karboxylsyre og 280,1 kg 10 piperazin i 242 1 3-metoxy-1-butanol opvarmedes under omrøring i 5 timer ved 125°C ( opvarmning med damp). Efter reaktionsblandingen var afkølet til ca. 100°C sattes der 531 1 sattes der 20%s vandig ppløsning af natriumhy-droxyd til blandingen, blandingen reguleredes til pH 15 7,5 med fortyndet eddikesyre og de fremkomne krystaller opsamledes ved hjælp af en centrifuge. Denne filtrering tog 1,5 time. De resulterende krystaller opløstes i en blanding af 1255 1 vand og 100 1 iseddikesyre, og efter behandling med 4 kg aktiveret kul filtreredes på et 20 "Spakler" filter af type UR-17-12 {filterdimensioner er 2 3 m ). Denne filtrering tog 2,5 timer.A mixture of 241.5 kg of ethyl 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 280.1 kg of piperazine in 242 l of 3-methoxy-1- butanol was heated under stirring for 5 hours at 125 ° C (heating with steam). After the reaction mixture was cooled to ca. At 100 ° C, 531 liters were added 20% aqueous sodium hydroxide solution to the mixture, the mixture was adjusted to pH 7.5 with dilute acetic acid and the resulting crystals were collected by centrifuge. This filtration took 1.5 hours. The resulting crystals were dissolved in a mixture of 1255 L of water and 100 L of glacial acetic acid and after treatment with 4 kg of activated charcoal was filtered on a 20 "Spacer" filter of type UR-17-12 (filter dimensions are 2 3 m). This filtration took 2.5 hours.
Filtratet reguleredes til pH 7,5 med 10%s vandig opløsning af natriumhydroxyd. De fremkomne krystaller opsamledes ved filtrering ved hjælp af en centrifuge, 25 vaskedes med vand og tørredes ved 80°C i 5 timer ved hjælp af en vifte. De tørrede krystaller omkrystalliseredes fra 2000 1 blanding diklormetan/ætanol 5:3 og tørredes ved hjælp af en vifte i 8 timer ved 80°C; der vandtes 202,8 kg (78,3%) norfloxacin.The filtrate was adjusted to pH 7.5 with 10% aqueous sodium hydroxide solution. The resulting crystals were collected by filtration using a centrifuge, washed with water and dried at 80 ° C for 5 hours using a fan. The dried crystals were recrystallized from 2000 L of 5: 3 dichloromethane / ethanol mixture and dried by a fan for 8 hours at 80 ° C; 202.8 kg (78.3%) of norfloxacin was obtained.
3030
Det viste sig ved HPLC at norfloxacin fremstillet på den kendte måde (foranstående afsnit A) indeholdt spor af biproduktet med formel VI trods flere ganges rensning; indholdet af dette biprodukt var ifølge HPLC-35 undersøgelserne fra 0,6% til 0,9% ved forskellige produktioner som beskrevet foran.It was found by HPLC that norfloxacin prepared in the known manner (preceding section A) contained traces of the by-product of Formula VI despite several times purification; the content of this by-product, according to the HPLC-35 studies, was from 0.6% to 0.9% in various productions as described above.
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I modsætning hertil indeholdt norfloxaxin fremstillet ved fremgangsmåden ifølge opfindelsen intet sådant biprodukt, idet det ikke frembringes ved den foreliggende fremgangsmåde.In contrast, norfloxaxine produced by the process of the invention contained no such by-product, since it is not produced by the present process.
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Ved forskellige fremstillinger af norfloxacin på den kendte måde som beskrevet i sammenligningseksemplet opnåedes udbytter i % som følger: 10 Rå syre med Norfloxacin med formel IV_j formel V, Regnet ud fra den . Renset forbin- : regnet ud rå syre med formel V delse ud fra ! fra ætyles- - ætylesteren medjIn various preparations of norfloxacin in the known manner as described in the comparative example, yields in% were obtained as follows: 10 Crude acid with Norfloxacin of formula IV, formula V, calculated from it. Purified compound: calculated from crude acid of formula A! from the ethyl ester - the ester ester medj
teren med Rå forb. Renset forb. formel I Ithe crude with raw compound purified compound formula I I
formel I____· 1 89,5 87,5 67,9 60,8 15 2 88,7 85,2 64,0 56,8 3 90,2 84,7 62,2 56,1 4 89,1 86,0 64,3 57,3 5 88,9 85,5 61,2 54,4 20 gns. 89,3 85,8 63,9 57,1formula I ____ · 1 89.5 87.5 67.9 60.8 15 2 88.7 85.2 64.0 56.8 3 90.2 84.7 62.2 56.1 4 89.1 86.0 64.3 57.3 5 88.9 85.5 61.2 54.4 20 Avg 89.3 85.8 63.9 57.1
Ved forskellige fremstillinger af norfloxacin ved fremgangsmåden ifølge opfindelsen som beskrevet i sammenligningseksemplet opnåedes udbytter i % som føl-25 ger:In various preparations of norfloxacin by the method of the invention as described in the comparative example, yields in% were obtained as follows:
Odbytte af norfloxacin, regnet ud fra ætylesteren med formel IOdor exchange of norfloxacin, calculated from the ethyl ester of formula I
Rå forb. Renset forb.Raw forb. Purified forb.
30 1 87,2 78,3 2 88,0 78,1 3 86,6 76,4 4 89,0 77,9 5 87,5 78,1 35--- gns. 87,5 77,6 730 1 87.2 78.3 2 88.0 78.1 3 86.6 76.4 4 89.0 77.9 5 87.5 78.1 35 --- 87.5 77.6 7
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Det fremgår således at der både med hensyn til fravær af forureningen med formel VI og med ‘hensyn til udbyttet af slutforbindelse opnås en væsentlig forbedring ved den industrielle fremstilling af norfloxacin.Thus, it appears that both in the absence of the contamination of Formula VI and in terms of the yield of the final compound a significant improvement is obtained in the industrial manufacture of norfloxacin.
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Eksempel 1 19,5 g vandfri piperazin og 16,8 g l-ætyl-6-fluor-7-klor-4-oxo-1,4-dihydrokinolin-3-karboxylsyreætylester sat-10 tes til 34 ml pyridin og blandingen kogtes under tilbagesvaling og omrøring i 5 timer. Reaktionsblandingen koncentreredes under nedsat tryk og remanensen opløstes i 100 ml kloroform. Kloroformlaget vaskedes med vand tre gange. Efter at kloroformlaget var tørret over vandfri magniumsulfat 1 5 afdampedes kloroformen under nedsat tryk og remanensen opløstes under opvarmning i benzen. Efter filtrering afkøledes benzenlaget. De udfældede krystaller omkrystalliseredes fra en blanding af 50 ml metylenklorid og iOO ml benzen hvorved der vandtes 17,3 g (88%s udbytte) 1-ætyl-20 6-fluor-7-(1-piperazinyl)-4-oxo-l,4-dihydroisokinolin-3- karboxylsyreætylester med smp. 178,5-180°C.Example 1 19.5 g of anhydrous piperazine and 16.8 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester were added to 34 ml of pyridine and the mixture was boiled reflux and stir for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in 100 ml of chloroform. The chloroform layer was washed with water three times. After the chloroform layer was dried over anhydrous magnesium sulfate, the chloroform was evaporated under reduced pressure and the residue dissolved under heating in benzene. After filtration, the benzene layer was cooled. The precipitated crystals were recrystallized from a mixture of 50 ml of methylene chloride and 100 ml of benzene to give 17.3 g (88% yield) of 1-ethyl-20-6-fluoro-7- (1-piperazinyl) -4-oxo-1 , 4-dihydroisoquinoline-3-carboxylic acid ethyl ester, m.p. 178.5 to 180 ° C.
Beregnet for C]_8H22FN30: C 62,31 H 6,22 N 12,03Calcd for C 18 H 22 FN 3 O: C 62.31 H 6.22 N 12.03
Fundet: C 62,23 H 6,38 N 12,10%.Found: C 62.23 H 6.38 N 12.10%.
__ MS (m/e) M+ 347 (beregnet '347) _i IR (KBr) 3320 cm ( ω, piperazinkerne N-H), 1729 cm (s, C=0 i ester), 1623 cm (s, C=0 i ring) NMR (6) 1,30 - 1,62 ppm (m, CH3.CH2-), 30 2,95-3,28 ppm (m, -CH2CH2-), 4,00 - 4,48 ppm (m, CH3.CH2-), 6,60 - 6,74, 7,83 - 8,03, og 8,29 ppm (m og s, =C-H) 35 Til en 90°C varm opløsning af 40 ml 6%s vandig natrium- hydroxyd sates 5 g af den ovenfor vundne ester. Efter henstand ved samme temperatur i 5 minutter afkøledes reaktionsbian- 8__ MS (m / e) M + 347 (calculated '347) _ in IR (KBr) 3320 cm (ω, piperazine sinks NH), 1729 cm (s, C = 0 in ester), 1623 cm (s, C = 0 in ring ) NMR (δ) 1.30 - 1.62 ppm (m, CH 3 CH 2 -), 2.95-3.28 ppm (m, -CH 2 CH 2 -), 4.00 - 4.48 ppm (m, CH3 CH2 -), 6.60 - 6.74, 7.83 - 8.03, and 8.29 ppm (m and s, = CH) 35 To a 90 ° C hot solution of 40 ml of 6% aqueous sodium hydroxide is added to 5 g of the ester obtained above. After standing at the same temperature for 5 minutes, the reaction mixture was cooled 8
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dingen i vand. Reaktionsblandingen indstilledes til pHthings in water. The reaction mixture was adjusted to pH
7,5 med fortyndet saltsyre for at opnå krystaller. Krystallerne omrørtes et øjeblik i 20 ml metanol, filtreredes fra, tørredes og omkrystalliseredes fra en blanding af 5 25 ml metylenklorid og 15 ml ætanol hvorved der vandtes 4,1 g (89%s udbytte) l-ætyl-6-fluor-7-(1-piperazinyl)-4-oxo-l,4-dihydrokinolin-3-karboxylsyre (norfloxacin) med smp.7.5 with dilute hydrochloric acid to obtain crystals. The crystals were stirred for a moment in 20 ml of methanol, filtered off, dried and recrystallized from a mixture of 25 ml of methylene chloride and 15 ml of ethanol to give 4.1 g (89% yield) of 1-ethyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (norfloxacin), m.p.
221-222°C.221-222 ° C.
1q Eksempel 2Example 2
En blanding af 18 ml pikolin, 10,3 g vandfri piper-azin og 8,9 g l-ætyl-6-fluor-7-klor-4-oxo-l,4-dihydrokino-lin-3-karboxylsyreætylester kogtes under tilbagesvaling og omrøring i 5 timer. Reaktionsblandingen koncentreredesA mixture of 18 ml of picoline, 10.3 g of anhydrous piperazine and 8.9 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester was refluxed. and stirring for 5 hours. The reaction mixture was concentrated
1 C1 C
under nedsat tryk og remanensen behandledes på samme måde som i eksempel 1 hvorved der vandtes 8,2 g (79%s udbytte) l-ætyl-6-fluor-7-(1-piperazinyl)-4-oxo-1,4-dihydrokinolin- 3-karboxylsyreætylester med smp. 178-180°C.under reduced pressure and the residue was treated in the same manner as in Example 1 to give 8.2 g (79% yield) of 1-ethyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1,4- dihydroquinoline-3-carboxylic acid ethyl ester with m.p. 178-180 ° C.
Til en blanding af 170 ml iseddikesyre og 170 ml 20 koncentreret saltsyre sattes der 4,3 g l-ætyl-6-fluor-7-(1-piperaziny1)-4-oxo-1,4-dihydrokinolin-3-karboxylsyre-ætylester og reaktionsblandingen koncentreredes under nedsat tryk. Remanensen opløstes i 10 ml vand og indstilledes til pH 7,5 med fortyndet natriumhydroxydopløsning. De ud-25 o e fældede krystaller oparbejdedes pa samme made som beskrevet i eksempel 1 hvorved der vandtes 3,3g (84%s udbytte) 1- ætyl-6-fluor-7-(1-piperaz iny1)-4-oxo-1,4-dihydrokinolin- 3-karboxylsyre (norfloxacin) med smp. 220,5-222 C.To a mixture of 170 ml glacial acetic acid and 170 ml of concentrated hydrochloric acid was added 4.3 g of 1-ethyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 10 ml of water and adjusted to pH 7.5 with dilute sodium hydroxide solution. The precipitated crystals were worked up in the same manner as described in Example 1 to give 3.3g (84% yield) of 1- ethyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (norfloxacin), m.p. 220.5-222 C.
3030
Eksempel 3Example 3
En blanding af 18 ml triætylamin, 10,3 g vandfri piperazin og 8,9 g l-ætyl-6-fluor-7-klor-4-oxo-l,4-dihydro-kinolin-3-karboxylsyreætylester kogtes under tilbagesvaling 35 og omrøring i 20 timer. Reaktionsblandingen koncentreredes under nedsat tryk, der sattes 30 ml kloroform til remanensen og afkøledes til 0°C til dannelse af krystaller. Krystal- 9A mixture of 18 ml of triethylamine, 10.3 g of anhydrous piperazine and 8.9 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester was refluxed for 35 hours. stirring for 20 hours. The reaction mixture was concentrated under reduced pressure, adding 30 ml of chloroform to the residue and cooled to 0 ° C to form crystals. Crystal- 9
DK 154763 BDK 154763 B
lerne filtreredes til udvinding af 2 g l-ætyl-6-fluor-7-klor-4-oxo-1,4-dihydrokinolin-3-karboxylsyreætylester.The clays were filtered to recover 2 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester.
Den ovenfor vundne filtrerede opløsning ekstraheredes med fortyndet saltsyre, saltsyrelaget neutraliseredes med 5 fortyndet natriumhydroxyd og den neutraliserede opløsning ekstraheredes med kloroform. Kloroformlaget vaskedes med vand og tørredes over vandfrit magniumsulfat og kloroformen afdampedes under nedsat tryk. Remanensen behandledes ved samme fremgangsmåde som i eksempel 1 hvorved der vandtes 10 7,4 g (71%s udbytte) l-ætyl-6-fluor-7-(1-piperazinyl)-4- oxo-1,4-dihydrokinolin-3-karboxylsyreætylester med smp. 178-180°C.The filtered solution obtained above was extracted with dilute hydrochloric acid, the hydrochloric acid layer was neutralized with dilute sodium hydroxide and the neutralized solution extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate and the chloroform was evaporated under reduced pressure. The residue was treated by the same procedure as in Example 1 to give 7.4 g (71% yield) of 1-ethyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3 -carboxylic acid ethyl ester with m.p. 178-180 ° C.
Det ovenfor vundne produkt hydrolyseredes som beskrevet i eksempel 1 og 2 hvorved der vandtes den tilsva-15 rende syre.The product obtained above was hydrolyzed as described in Examples 1 and 2 to give the corresponding acid.
Eksempel 4 10,3 g vandfri piperazin og l-ætyl-6-fluor—7-klor-20 4-oxo-1,4-dihydrokinolin-3-karboxylsyreætylester .sattes til en blanding af 9 ml pyridin og 18 ml toluen og blandingen kogtes under tilbagesvaling og omrøring i '5 timer.Example 4 10.3 g of anhydrous piperazine and 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester were added to a mixture of 9 ml of pyridine and 18 ml of toluene and the mixture. was refluxed and stirred for 5 hours.
Den samme procedure som beskrevet i eksempel 1 blev fulgt hvorved der vandtes 8,4 g (81%s udbytte) l-ætyl-'6—f luor-25 7-(1-piperazinyl)-4-oxo-1,4-dihydrokinolin-3-karboxylsyre ætylester med smp. 178,5-180°C.The same procedure as described in Example 1 was followed to give 8.4 g (81% yield) of 1-ethyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1,4-carboxylic acid. dihydroquinoline-3-carboxylic acid ethyl ester with m.p. 178.5 to 180 ° C.
Den ovennævnte ætylester hydrolyseredes på samme måde som beskrevet i eksempel 1 og 2 til dannelse af norfloxacin.The above ethyl ester was hydrolyzed in the same manner as described in Examples 1 and 2 to form norfloxacin.
3030
Eksempel 5Example 5
En blanding af 1,7 g vandfri piperazin og 1,4 g l-ætyl-6-fluor-7-klor-4-oxo-1,4-dihydrokinolin-3-karboxy1- syremetylester i 3 ml pyridin kogtes under tilbagesva-35 ling og omrøring i 5 timer. Reaktionsblandingen afkøledes til dannelse af rå krystaller. De rå krystaller omkrystal- 10A mixture of 1.7 g of anhydrous piperazine and 1.4 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester in 3 ml of pyridine was boiled under reflux. stir and stir for 5 hours. The reaction mixture was cooled to give crude crystals. The crude crystals recrystallized 10
DK 154763 BDK 154763 B
liseredes fra en blanding af metylenklorid og metanol hvorved der vandtes 1,55 g (77,5%s udbytte) l-ætyl-6-fluor- 7-(l-piperazinyl)-4-oxo-l,4-dihydrokinolin-3-karboxylsyre-metylester med smp. 179-181°C.was lysed from a mixture of methylene chloride and methanol to give 1.55 g (77.5% yield) of 1-ethyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3 -carboxylic acid methyl ester with m.p. 179-181 ° C.
5 Beregnet for C^H^FN^Ci^: C 60,87 H 6,19 N 12,22Calculated for C C ^H H ^N ^C Ci ^: C, 60.87; H, 6.19; N, 12.22
Fundet: C 61,25 H 6,05 N 12,60%.Found: C 61.25 H 6.05 N 12.60%.
MS (m/e) M+ 333 (beregnet 333) IR (KBr) 1712 cm"1 (C=0 i ester), 1631 cm ^ (C=0 i ring) 1 0 NMR (S) 1,50 (t,-CH2CH3), 2,08 (s, NH), 2,90 - 3,35 Tm7-CH2CH2-), 3,89 (S,-0CH3), 4,18 (q,-CH2CH3), 6,67 (d, 8-H), 7,94 (d, 5-H), 8,33 (s, 2-H) 1 5 Den ovenfor vundne metylester hydrolyseredes på samme måde som beskrevet i eksempel 1 hvorved der vandtes 1,1 g (85,2%s udbytte) l-ætyl-6-fluor-7-(l-piperazinyl)- l,4-dihydrokinolin-3-karboxylsyre (norfloxacin) med smp.MS (m / e) M + 333 (calculated 333) IR (KBr) 1712 cm "1 (C = 0 in ester), 1631 cm ^ ((C = 0 in ring) 10 NMR (S) 1.50 (t, -CH2CH3), 2.08 (s, NH), 2.90 - 3.35 Tm7-CH2CH2-), 3.89 (S, -OCH3), 4.18 (q, -CH2CH3), 6.67 ( d, 8-H), 7.94 (d, 5-H), 8.33 (s, 2-H). The above methyl ester obtained was hydrolyzed in the same manner as described in Example 1 to give 1.1 g. (85.2% yield) 1-Ethyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid (norfloxacin), m.p.
220,5-221,5°C.220.5 to 221.5 ° C.
20 25 30 3520 25 30 35
DK 154763 BDK 154763 B
.110.11
Eksempel 6Example 6
En blanding af 10 g l-ætyl-6-fluor-7-klor-4-oxo- l,4-dihydrokinolin-3-karboxylsyreætylester, 11,6 g vandfri piperazin og 10 ml 3-metoxybutanol kogtes under tilba-5 gesvaling ved 125°C i 5 timer. Efter afkøling sattes der 22 ml 20%s natriumhydroxydopløsning til reaktionsblandingen og der opvarmedes til 90°C i 30 minutter. Efter afkøling sattes der 35 ml vand til reaktionsblandingen, reaktionsblandingen indstilledes til pH 7,5 med fortyndet eddikesyre-10 opløsning, de fremkomne krystaller filtreredes. Krystallerne opløstes i en opløsning af 42 ml eddikesyre i 52 ml vand, efter behandling med aktivt kulstof filtreredes opløsningen og der sattes 4,5 ml svovlsyre til filtratet.A mixture of 10 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester, 11.6 g of anhydrous piperazine and 10 ml of 3-methoxybutanol was boiled under reflux at reflux. 125 ° C for 5 hours. After cooling, 22 ml of 20% sodium hydroxide solution was added to the reaction mixture and heated to 90 ° C for 30 minutes. After cooling, 35 ml of water was added to the reaction mixture, the reaction mixture was adjusted to pH 7.5 with dilute acetic acid solution, the crystals obtained were filtered. The crystals were dissolved in a solution of 42 ml of acetic acid in 52 ml of water, after treatment with activated carbon the solution was filtered and 4.5 ml of sulfuric acid was added to the filtrate.
Det fremkomne svovlsyresalt omkrystalliseredes fra vand, 15 De vundne krystaller opløstes i en opløsning af Z0%s natriumhydroxydopløsning (9 ml) i 110 ml vand og filtreredes. Filtratet indstilledes til pH 7,5, de fremkomne krystaller vaskedes med vand. Disse krystaller sattes til 100 ml ætanol, omrørtes i 1 time og tørredes hvorved der vandtes 9,2 g 20 (85,8%s udbytte, beregnet fra udgangsmaterialet) 1-ætyl- 6-fluor-7-(1-piperaziny1)-4-oxo-1,4-dihydrokinolin-3-karb-oxylsyre (norfloxacin) med smp. 221-222 C.The resulting sulfuric acid salt was recrystallized from water. The obtained crystals were dissolved in a solution of ZO% sodium hydroxide solution (9 ml) in 110 ml of water and filtered. The filtrate was adjusted to pH 7.5, the crystals obtained were washed with water. These crystals were added to 100 ml of ethanol, stirred for 1 hour and dried to give 9.2 g of 20 (85.8% yield, calculated from the starting material) 1-ethyl-6-fluoro-7- (1-piperazinyl) - 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (norfloxacin), m.p. 221-222 C.
Claims (2)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12302480 | 1980-09-05 | ||
| JP55123024A JPS5762259A (en) | 1980-09-05 | 1980-09-05 | Preparation of substituted quinolinecarboxylic acid derivative |
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| Publication Number | Publication Date |
|---|---|
| DK380681A DK380681A (en) | 1982-03-06 |
| DK154763B true DK154763B (en) | 1988-12-19 |
| DK154763C DK154763C (en) | 1989-06-26 |
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| DK380681A DK154763C (en) | 1980-09-05 | 1981-08-27 | PROCEDURE FOR THE PREPARATION OF NORFLOXACIN |
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|---|---|
| US (1) | US4472579A (en) |
| JP (1) | JPS5762259A (en) |
| KR (1) | KR870001944B1 (en) |
| AR (1) | AR226917A1 (en) |
| AT (1) | AT380009B (en) |
| AU (1) | AU540205B2 (en) |
| BE (1) | BE890223A (en) |
| CA (1) | CA1214466A (en) |
| CH (1) | CH646697A5 (en) |
| DE (1) | DE3135125A1 (en) |
| DK (1) | DK154763C (en) |
| ES (2) | ES505207A0 (en) |
| FI (1) | FI77854C (en) |
| FR (1) | FR2489821B1 (en) |
| GB (1) | GB2085875B (en) |
| GR (1) | GR74304B (en) |
| HU (1) | HU187356B (en) |
| IE (1) | IE51540B1 (en) |
| IN (1) | IN155106B (en) |
| IT (1) | IT1168168B (en) |
| LU (1) | LU83609A1 (en) |
| MX (1) | MX7101E (en) |
| NL (1) | NL193375C (en) |
| NO (1) | NO157699C (en) |
| NZ (1) | NZ198295A (en) |
| PH (1) | PH17837A (en) |
| PT (1) | PT73571B (en) |
| SE (1) | SE442402B (en) |
| ZA (1) | ZA815207B (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3142854A1 (en) * | 1981-10-29 | 1983-05-11 | Bayer Ag, 5090 Leverkusen | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-CHINOLINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
| US4670444B1 (en) * | 1980-09-03 | 1999-02-09 | Bayer Ag | and-naphthyridine-3-carboxylic acids and antibacte7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-rial agents containing these compounds |
| JPS59122470A (en) * | 1982-12-27 | 1984-07-14 | Dai Ichi Seiyaku Co Ltd | Preparation of quinoline-3-carboxylic acid derivative |
| DE3306771A1 (en) * | 1983-02-25 | 1984-08-30 | Bayer Ag, 5090 Leverkusen | CHINOLONIC CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| DE3318145A1 (en) * | 1983-05-18 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-6,8-DIFLUOR-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
| AU553415B2 (en) * | 1983-09-19 | 1986-07-17 | Abbott Japan Co., Ltd. | 6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids |
| DE3504643A1 (en) * | 1985-02-12 | 1986-08-14 | Bayer Ag, 5090 Leverkusen | 1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO-7- (4- (2-OXO-1,3-DIOXOL-4-YL-METHYL) -1-PIPERAZINYL) -3-QUINOLINE CARBONIC ACIDS, METHOD FOR YOURSELF PRODUCTION AND THIS ANTIBACTERIAL AGENT |
| HUT40429A (en) * | 1985-04-29 | 1986-12-28 | Chinoin Gyogyszer Es Vegyeszet | Process for production of salts of derivatives of kynolin carbonic acid |
| DE3525108A1 (en) * | 1985-06-07 | 1986-12-11 | Bayer Ag, 5090 Leverkusen | ANTIBACTERIAL EFFECT OF CHINOLON CARBON ACID ESTERS |
| DE3525335A1 (en) * | 1985-07-16 | 1987-01-22 | Bayer Ag | EMBONATES OF CHINOLON CARBONIC ACIDS AND THEIR DERIVATIVES |
| DE3542002A1 (en) * | 1985-11-28 | 1987-06-04 | Bayer Ag | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7- (1-PIPERAZINYL) -3-QUINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR ANTIBACTERIAL AGENTS CONTAINING THEM |
| HU196218B (en) | 1985-12-09 | 1988-10-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing quinoline carboxylic acid boric acid anhydrides |
| CA1306750C (en) | 1985-12-09 | 1992-08-25 | Istvan Hermecz | Process for the preparation of quinoline carboxylic acide |
| YU46099B (en) * | 1987-12-31 | 1992-12-21 | Krka Tovarna Zdravil | PROCESS FOR PREPARING 1-SUBSTITUTED 6-FLUORO-4-OXO-7- 1-PIPERAZINYL) -1 |
| SI9200377A (en) | 1992-12-11 | 1994-06-30 | Krka | Process for the preparation of 1-substituted 6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxilic acid, novel intermediate used in this process and process for its preparation |
| US6584615B1 (en) * | 1998-11-06 | 2003-07-01 | Mission Hockey Company | Asymmetrical hockey glove system with articulated locking thumb |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US2504875A (en) * | 1945-06-04 | 1950-04-18 | Us Sec War | Method for producing 4-hydroxyquinolines |
| US4017622A (en) * | 1972-12-18 | 1977-04-12 | Dainippon Pharmaceutical Co., Ltd. | Piperazine derivatives |
| JPS5732059B2 (en) * | 1974-02-09 | 1982-07-08 | ||
| FI311974A (en) * | 1973-10-26 | 1975-04-27 | Dainippon Pharmaceutical Co | |
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| US4292317A (en) * | 1977-09-20 | 1981-09-29 | Laboratorie Roger Bellon | 1,4-Dihydro-quinoline-3-carboxylic acid derivatives, process for their preparation and compositions containing them |
| JPS5466686A (en) * | 1977-09-20 | 1979-05-29 | Dainippon Pharmaceut Co Ltd | Quinoline-3-carboxylic acid derivative, its preparation, and pharmaceutical composition containig the same |
| JPS54141286A (en) * | 1978-04-14 | 1979-11-02 | Matsuo Kogyo | Spool detachable system in spinning reel for fishing |
| JPS54138582A (en) * | 1978-04-19 | 1979-10-27 | Kyorin Seiyaku Kk | Substituted quinolinecarboxylic acid |
| JPS5540656A (en) * | 1978-09-19 | 1980-03-22 | Kyorin Pharmaceut Co Ltd | Substituted quinoline-carboxylic acid derivative |
| JPS5845426B2 (en) * | 1978-09-29 | 1983-10-08 | 杏林製薬株式会社 | Substituted quinoline carboxylic acid derivatives |
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